Elevated levels of low-density lipoprotein (LDL)-cholesterol has been recognized as the most important risk factor for Coronary Artery Disease (CAD). The most effective method of LDL-cholesterol lowering is the administration of inhibitors of HMG-CoA reductase (statins), a rate-limiting key enzyme of the cholesterol synthesis pathway. Since the discovery of compactin and lovastatin, both of which were compounds of microbial origin, primary and secondary preventive measures have been established in several statin trials to help prevent future events of CAD by lowering LDL-cholesterol levels. To date, pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin and atorvastatin have been used in clinical practice.
Several landmark studies demonstrate that primary and secondary prevention strategies with lipid-lowering therapies provide significant reductions in cardiovascular morbidity and mortality. The Helsinki Heart Study demonstrated the benefit of lipid lowering in asymptomatic, middle-aged men with primary hypercholesterolemia. Treatment with gemfibrozil increased HDL cholesterol and lowered LDL, cholesterol; this improved lipid profile was associated with a significant 34% reduction in CHD risk over the 5-year follow-up period.
The Scandinavian Simvastatin Survival Study (4S) and the Cholesterol and RecurrentEvents (CARE) trial demonstrated the benefit of lipid lowering with statins in patients with established CAD. In 4S, simvastatin treatment reduced LDL cholesterol by 35% and increased HDL cholesterol by 8%. This was associated with significant 30% and 42% reductions in all-cause and coronary mortality risk, respectively, and a 34% reduction in major coronary events over the mean 5.4-year follow-up period. In the CARE study, pravastatin significantly reduced risk for fatal coronary events or nonfatal MI by 24% over a 5-year period. Taken together, these studies demonstrate that a reduction in LDL cholesterol of approximately 25%-35% significantly reduces risk for cardiovascular morbidity and mortality in patients with or without established CAD.
Several recent studies using quantitative coronary angiography demonstrate that lipid lowering slows progression of coronary atherosclerosis in CAD patients. In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), fluvastatin was administered to patients with angiographic CAD who had baseline LDL cholesterol levels of 115-190 mg/dL. Fluvastatin reduced LDL cholesterol by 24% and significantly reduced progression of coronary atherosclerosis over the 2.5-year follow-up period. In the Pravastatin Limitation of Atherosclerosis in the Coronary Artery (PLAC I) study, pravastatin was administered to CAD patients with baseline LDL cholesterol levels of 130-190 mg/dL. Pravastatin significantly reduced LDL cholesterol by 28% and atherosclerotic progression by 40% over the 3-year follow-up. As coronary atherosclerosis progresses, interventional procedures, such as balloon angioplasty, must be performed to reduce cardiac risk. Therefore, the Atorvastatin Versus Revascularization Treatments (AVERT) study was designed to ascertain if aggressive lipid lowering with atorvastatin can be used as an alternative to angioplasty or other catheter-based revascularization procedures in patients with significant CAD. The primary end point in this ongoing 18-month, open-label trial is the incidence of ischemic events.
The statins, in general are well tolerated during long-term use as evidenced by results from the major outcomes studies. The most serious adverse event associated with statins is myopathy, which occurs in 0.2% or less of treated patients. Myopathy is characterized by myalgia, muscle tenderness and weakness, and marked elevation in creatine phosphokinase to 10 or more times the upper limits of normal (ULN). In rare cases, myopathy may progress to rhabdomyolysis with acute renal failure. Risk for myopathy and rhabdomyolysis is increased by concomitant use of statins with gemfibrozil, cyclosporine, erythromycin, niacin, or azole antifungal agents. In approximately 1%-2% of patients, statins cause persistent elevations in liver function enzymes that are 3 times greater than the ULN. The incidence of elevated liver enzymes increases with higher statin doses. For example, during clinical trials with atorvastatin, elevated liver enzymes were found in 0.2% of patients receiving doses of 10 or 20 mg, 0.6% of those receiving 40 mg, and 2.3% of those receiving 80 mg. In general, a reduction in dose or discontinuation of statin treatment results in the return of liver enzymes to baseline levels.
While all statins have been associated with very rare reports of rhabdomyolysis, cases of fatal rhabdomyolysis in association with the use of cerivastatin have been reported significantly more frequently than for other approved statins. Fatal rhabdomyolysis reports with cerivastatin have been reported most frequently when used at higher doses, when used in elderly patients, and particularly, when used in combination with gemfibrozil (LOPID and generics), another lipid lowering drug. FDA has received reports of 31 U.S. deaths due to severe rhabdomyolysis associated with use of cerivastatin, 12 of which involved concomitant gemfibrozil use.
The rare rhabdomyolysis is presumed to be the result of higher level of systemic exposure of statins. Therefore HMG-CoA-reductase inhibitors with high first-pass metabolism and/or short plasma half-life would be desirable, since they will have limited systemic exposure and more predictable metabolic profile.